Proteolysis is a cleavage event of a protein that commonly occurs to serve several biological purposes such as zymogen activation, protein degradation, and immune response[1-3]. Most proteolytic cleavage event occur in the classical secretory pathway, which involves the passage of proteins targeted for post-translational modifications through the Endoplasmic Reticulum (ER) and trans-Golgi network. The main proteases required for proteolysis in the intracellular compartment include enzymes from signal peptidases (SP), signal peptide peptidases (SPP), and pro-protein convertase (PC) families[4-6].
Many proteins are synthesized with signal sequence or signal targeting for secretion or site-specific transport. Most signal sequences are about 20-30 amino acids in the N-terminus of a protein, and they are often cleaved by SP or SPP upon the transverse of newly translated proteins in the lumen of the ER. Moreover, proteins can be further cleaved by PC such as Furin or PC1 in order to render the protein functional or active. The classic example of such cleavage processing by SP, SPP, and PC is the cleavage of pre-pro-insulin by SP or/and SPP into its inactive pro-insulin, which will further be cleaved by PC into active insulin before being transported across the cell membrane as illustrated in FIG. 1[37].
Despite the fewer events that are present in cells, proteolysis events are also known to occur in the extracellular portion of the cells, granted that the event might produce different purposes than its intracellular counterpart. Some examples of extracellular proteolysis include the cleavage of E-Cadherin by ADAM-10 protease and the cleavage of Sialic Acid receptor protein by Neuraminidase (NA) in Influenza Virus budding[36]. Another prominent group of proteases that cleaves substrates in the extracellular membrane is Matrix Metalloproteases (MMPs).
MMPs have been of tremendous clinical significance due to recent evidence of their roles in the progression of cancer, atherosclerosis, aneurism, and arthritis[7,8]. MMP-14 is a ubiquitously-expressed cell surface protease known to activate several soluble MMPs (s-MMPs) via extracellular proteolysis. Active s-MMPs are then used for the restructuring of the extracellular matrix (ECM) that could facilitate cell migration and development. MMP-14 is known to be highly expressed in cancer tissues, as cells require constant remodeling of the ECM to accommodate fast replication and migration that leads to metastasis.